Megalin is a cell membrane protein also known as Low Density Lipoprotein (LDL) receptor-related protein 2 (LRP-2) or Glycoprotein 330 (gp 330) and is a large membrane-type single transmembrane-type glycoprotein with a molecular weight of approximately 600 KDa. Megalin has an extracellular region having four functional domains on the N-terminal side, a short intracellular region on the C-terminal side, and a single cell transmembrane region between the two. Megalin functions as an endocytosis receptor and takes in substances (megalin ligands) which bind to the extracellular region thereof into the cell. The expression of megalin in the bodies of mammals has been confirmed in the kidney proximal tubule epithelial cells (primarily, the luminal membrane), the inner ear epithelial cells, the testes, the neural ectoderm, and the like. In particular, in the kidney proximal tubule epithelial cells, glomerular filtered proteins, administered drugs, or the like bind to the extracellular region of megalin and are taken into the cell by endocytosis (for example, refer to NPL 1 and 2). For example, in the kidney proximal tubule epithelial cells, megalin-mediated endocytosis has a function of preventing physical decline by reabsorbing biological factors in the kidney proximal tubule.
A large number of biological factors, drugs, and the like have been reported as megalin ligands. Specific reported examples include albumin, aminoglycosides, amylase, angiotensin II, angiotensin 1-7, apolipoprotein B, apolipoprotein E, apolipoprotein H, apolipoprotein J (Clusterin), apolipoprotein M, aprotinin, bone morphogenetic protein 4, calcium ions, cathepsin B, coagulation factor VIII, connective tissue growth factor (CTGF), cytochrome C, cystatin C, epidermal growth factor (EGF), folate binding protein, galactosidase A, gelsolin, hemoglobin, insulin, insulin-like growth factor I (IGF-I), lactoferrin, leptin, lipoprotein lipase, liver-type fatty acid binding protein, Lp (a), lysozyme, metallothionein, α1-microglobulin, β2-microglobulin, myoglobin, neutrophil gelatinase associated lipocalin (NGAL), odorant binding proteins, parathyroid hormones, pancreatitis associated protein 1 (PAP-1), plasminogen, plasminogen activator inhibitor type 1 (PAI-1), plasminogen activator inhibitor type 1 urokinase (uPAI-1), plasminogen activator inhibitor type 1 tissue plasminogen activator (tPAI-1), polymyxin B, prolactin, pro-urokinase, recombinant activated factor VIIa (rFVIIa), retinol binding protein (RBP), selenoprotein p, seminal vesicle secreted protein II, sex hormone-binding globulin, sonic hedgehog protein, thyroglobulin, transcobalamin-vitamin B12, transthyretin, trichosanthin, vitamin d-binding protein, or the like (for example, refer to NPL 3).
These drugs and metabolites thereof may cause severe renal impairment. There are a variety of routes in the pathogenesis of renal impairment; however, the reabsorption mechanism through megalin is known to be one factor. For example, polymyxin B of the polymyxins, which are cyclic peptide antibiotics, has been shown to cause cell damage by being taken into the cell by endocytosis after binding to megalin. In addition, aminoglycoside antibiotics such as gentamicin are taken into the cell by endocytosis after binding to megalin; however, it is reported that an effect of suppressing nephrotoxicity caused by gentamicin aminoglycoside antibiotics is obtained by co-administration of lysozyme, aprotinin, and cytochrome C, which are megalin ligands (for example, refer to PTL 1).
There are cases in which renal impairment is caused by biological factors. It is known that, in a situation where an excess of albumin is discharged in primary urine and the reabsorption function due to megalin is pathologically increased, the kidney proximal tubular cells are damaged, which leads to chronic renal impairment such as diabetic nephropathy. In addition, for example, in NPL 4, when the kidney glomerular epithelial cells (podocytes) are destroyed by the administration of LMB2, which is an immunotoxin, to cause filtration function failure, the renal tubular cells are damaged by cellular stress as a result of albumin discharged in large amounts in primary urine being excessively taken into the cells via megalin; however, it is reported that such cell damage does not occur in renal tubular cells in which megalin is not expressed in a megalin mosaic-type knockout mouse (that is, a mouse where only a part of the megalin expression in the renal tubular cells is lacking).
On the other hand, cilastatin (cilastatin; (Z)-7-[[(R)-2-amino-2-carboxyethyl] thio]-2-[[[(S)-2,2-dimethylcyclopropyl] carbonyl] amino]-2-heptenoic acid) has an inhibitory activity with respect to dehydropeptidase-I (DHP-I), which is a metabolic enzyme present in the kidney proximal tubule brush border membrane. Anti-microbial activity is not recognized in cilastatin; however, since the carbapenem-based antibiotic imipenem is subject to degradation by DHP-I and the metabolites thereof greatly damage the kidney proximal tubule, mixtures of imipenem and cilastatin are used as injectable solutions with the object of preventing renal impairment due to these metabolites.
PTL 2 reports that cilastatin has an effect of attenuating the toxicity of drugs having a number of nephrotoxicities. The same document reports that, in practice, when cisplatin, which is an anti-cancer drug, is co-administered with cilastatin to rats, the nephrotoxicity was improved, and shows that cilastatin has the possibility of reducing the nephrotoxicity by inhibiting the transport path into the cells via cholesterol rafts.
On the other hand, it is widely known that inner ear disorders (tinnitus, dizziness, and hearing loss) are caused as a side effect of using certain types of antibiotics (aminoglycoside drugs such as gentamicin, and glycopeptide anti-microbial agents such as vancomycin) and anti-cancer drugs such as cisplatin (NPL 6).
In addition, it is known that many agents which cause inner ear disorders function as megalin ligands and that megalin is localized in the inner ear epithelial cells (NPL 7).